Positron emission tomography (PET) is a non-invasive diagnostic technique of rapidly growing importance in the field of oncology. Since molecular events associated with cancer are directly observed using this method, custom tracers allow more specific identification of malignancies than simple anatomy-based imaging. An additional advantage of PET is an order of magnitude greater sensitivity than the single photon computerized tomography method used with gamma emitters (e.g. 99 mTc labeled probes).
The ideal tracer probe for imaging cancer would have the following characteristics: 1) it would accumulate specifically in targeted cells, 2) it would clear rapidly from blood and surrounding tissues not associated with the tumor, 3) the attachment of the radionuclide would not substantially diminish the affinity of the tracer molecule for its target, 4) the radionuclide would not be easily dissociated from the tracer molecule in vivo, 5) given the short half-life of positron emitting isotopes, the protocol for introducing the radionuclide into the probe should be as quick and efficient as possible.
The most commonly used isotope for PET is 18F, which is produced by proton bombardment of 18OH2 and has a comparatively long half life of 110 minutes. In the majority of clinical PET scans, the tracer probe is 2-18F-2-deoxy-D-glucose (FDG) (“Positron Emission Tomography with [18F]-FDG in Oncology.” J. N. Talbot, Y. Petegnief, K. Kerrou, F. Montravers, D. Grahek, N. Younsi, Nuclear Instruments and Methods in Physics Research A 2003, 504, 129), which is recognized by cells as glucose and taken up, but can not be utilized. FDG thus accumulates in the cells and a metabolic image of the tumor is obtained.
There are however a number of disadvantages to the use of FDG. First, it gives no direct indication of the neoplastic character of the lesion. Second, well-differentiated and slow-growing tumors are often not detected. Third, although it is highly useful for the management of certain cancers (e.g. lung, melanoma), it is less effective for others, e.g. those of the brain, where background glucose uptake is also rapid.
A potential answer to these issues can be found in the labeling of ligands which are specifically recognized by particular cancer cells. Since these can be cell-surface receptor proteins or even macromolecules (e.g. antibodies, diabodies, minibodies), there is substantially more leeway for the attachment of the label, and indeed macrocyclic 64Cu and 68Ga complexes have been developed in this context which would be much too large for the labeling of glucose (“Targeting Peptides and Positron Emission Tomography.” H. Lundqvist, V. Tolmachev, Biopolymers 2002, 66, 381). An advantage of using metal-macrocycle chelation is that the synthetic work required (i.e. attachment of the label to the molecular probe) can be done before the arrival of the radionuclide, which is simply complexed by the chelator-tracer conjugate and is ready for use. Unfortunately, 64Cu and 68Ga are far less readily available than 18F, which limits their widespread application in both research and therapy.
The practical scope for recognition and binding of anions is considerably narrower than that for metal cations (“Anion Recognition and Sensing: The State of the Art and Future Perspectives.” P. D. Beer, P. A. Gale, Angew. Chem. Int. Ed. 2001, 40, 486). One reason for this is because concentrations of negative potential are more accessible and manageable on the molecular scale than concentrations of positive potential. Thus while examples of electron wells abound in the form of easily manipulable heteroatom arrays, localized electron deficits involve Lewis acidic sites which are less conveniently integrated into receptor design than the common nonmetals, and are generally incompatible with the only other vectorial noncovalent interaction relevant to anions, i.e., hydrogen bonding.
Aromatic rings are intuitively sources of electron density, and much work has been done on their interaction with cations. However, heterocyclic and perfluorinated rings show a minimum in electrostatic potential at their centroids, thereby making a favorable interaction between such rings and anions possible. Using high level quantum mechanical modeling (MP2/6-31G*), we found an interaction on the order of 10 kcal mol-1 for s-triazine complexes with fluoride and chloride as the representative anions (“Anion-Aromatic Bonding: A Case for Anion Recognition by π-Acidic Rings.” M. Mascal, A. Armstrong, M. D. Bartberger, J. Am. Chem. Soc. 2002, 124, 6274). The optimized triazine centroid . . . anion distances for fluoride and chloride were about 2.6 and 3.2 Å, respectively.
Since present techniques for labeling peptides with 18F are laborious and not yet of clinical value, the best case scenario would be a system which achieved customized imaging using cell-line specific peptides, and incorporated an 18F− complexing agent to disinvolve chemical transformations from the labeling process. Surprisingly, the present invention meets this and other needs.